1. Academic Validation
  2. Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic Pharmacokinetics

Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic Pharmacokinetics

  • Cell Mol Gastroenterol Hepatol. 2022;13(2):383-404. doi: 10.1016/j.jcmgh.2021.09.004.
Bernhard Texler 1 Andreas Zollner 2 Vera Reinstadler 3 Simon J Reider 4 Sophie Macheiner 2 Barbara Jelusic 5 Alexandra Pfister 2 Christina Watschinger 4 Nicole Przysiecki 2 Herbert Tilg 6 Herbert Oberacher 3 Alexander R Moschen 7
Affiliations

Affiliations

  • 1 Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Daniel Swarovski Laboratory, Medical University Innsbruck, Innsbruck, Austria.
  • 2 Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria.
  • 3 Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria.
  • 4 Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Internal Medicine 2 (Gastroenterology and Hepatology), Kepler University Hospital, Faculty of Medicine, Johannes Kepler University Linz, Linz, Austria.
  • 5 Institute of Pathology, Medical University of Graz, Graz, Austria.
  • 6 Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria.
  • 7 Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Internal Medicine 2 (Gastroenterology and Hepatology), Kepler University Hospital, Faculty of Medicine, Johannes Kepler University Linz, Linz, Austria. Electronic address: alexander.moschen@jku.at.
Abstract

Objective: By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ulcerative colitis many aspects concerning its mode of action and pharmacokinetics remain unresolved.

Design: We studied tofacitinib's impact on various primary human innate and adaptive immune cells. In-depth in vivo studies were performed in dextran sodium sulfate-induced colitis in mice. Immune populations were characterized by flow cytometry and critical transcription factors and effector cytokines were analyzed. Pharmacokinetics of tofacitinib was studied by liquid chromatography-tandem mass spectrometry.

Results: Tofacitinib inhibited proliferation in CD4+ and CD8+ T cells along with Th1 and Th17 differentiation, while Th2 and regulatory T cell lineages were largely unaffected. Monocytes and macrophages were directed toward an anti-inflammatory phenotype and cytokine production was suppressed in intestinal epithelial cells. These findings were largely reproducible in murine cells of the inflamed mucosa in dextran sulfate sodium colitis. Short-term treatment with tofacitinib had little impact on the mouse microbiota. Strikingly, the degree of inflammation and circulating tofacitinib levels showed a strong positive correlation. Finally, we identified inflammation-induced equilibrative nucleoside transporters as regulators of tofacitinib uptake into leukocytes.

Conclusions: We provide a detailed analysis of the cell-specific immune-suppressive effects of the JAKis tofacitinib on innate and adaptive immunity and reveal that intestinal inflammation critically impacts tofacitinib's pharmacokinetics in mice. Furthermore, we describe an unappreciated mechanism-namely induction of equilibrative nucleoside transporters-enhancing baseline cellular uptake that can be inhibited pharmaceutically.

Keywords

JAK inhibitor; inflammatory bowel disease; mucosal inflammation; pharmacokinetics; tofacitinib.

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